The present invention relates to manufacture of camptothecin derivatives therapeutically useful as anti-cancer drugs, in particular the camptothecin derivative irinotecan and salts thereof. More particularly, the invention relates to a novel intermediate and to a process for preparing a camptothecin derivative via that intermediate.
U.S. Pat. No. 6,121,451 to Henegar and Sih, incorporated herein by reference, discloses a process for preparing the antineoplastic drug irinotecan, also known as 7-ethyl-10-hydroxycamptothecin 10-[1,4xe2x80x2-bipiperidine]-1xe2x80x2-carboxylate or CPT-11 free base. In the disclosed process, a compound therein identified as 14CPT (I) is first reacted with 1-(4-hydroxy-2-aminophenyl)-1-propanone (II) to form an intermediate compound (III), which is then reacted with 4-piperidinopiperidinecarbamyl chloride (IV) to produce CPT-11 free base (V), as shown schematically below. 
Alternative materials and methods for preparing irinotecan and other therapeutically useful camptothecin derivatives are desired in the art.
Novel compounds are now provided, having the formula (VI) 
where R1 is hydrogen, an alkyl aralkyl, hydroxymethyl, carboxymethyl, acyloxymethyl or trialklsilyl group, or a group xe2x80x94CH2NR3R4 where N is a linking nitrogen atom and where R3 and R4 are as defined hereinbelow. Also provided are salts of the compounds of formula (VI) with pharmaceutically acceptable anions.
Options for R3 and R4 are:
(a) R3 and R4 are independently selected from hydrogen and alkyl, alkenyl, hydroxyalkyl and alkoxyalkyl groups;
(b) R3 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group, and R4 is xe2x80x94COR5 where R5 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group; or
(c) R3 and R4 taken together with the linking nitrogen atom form a saturated 3- to 7-member heterocyclic group.
Compounds of the invention are useful intermediates in a process to prepare camptothecin derivatives of formula (VII) 
where R1 is as defined above and R2 is hydrogen or an alkyl group, preferably hydrogen.
In a preferred embodiment R1 is an ethyl group and R2 is hydrogen. According to this embodiment, the novel compound of formula (VI) is 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate, which is a useful intermediate in a process to prepare irinotecan (V) and salts thereof, for example the hydrochloride salt CPT-11. Thus, according to another embodiment of the invention, a process is provided comprising a step of reacting 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate with the compound of formula (I) above to form irinotecan.
In yet another embodiment of the invention, a process is provided for preparing a compound of formula (VI). This process can be illustrated with respect to the compound of formula (VI) where R1 is an ethyl group, i.e., 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate. In this case the process comprises a step of reacting 1-(4-hydroxy-2-aminophenyl)-1-propanone (II) with 4-piperidinopiperidinecarbamyl chloride (IV) to form 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate. By appropriate modification of compound (II) one of skill in the art will be able to make other compounds of formula (VI) of the invention.
Typically, an irinotecan or CPT-11 product prepared by a process using 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate will contain at least a detectable amount of that compound. Thus, in yet another embodiment of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of irinotecan and/or a salt thereof and at least a detectable amount of 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate and/or a salt thereof. By its presence in a detectable amount, 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate is useful as an analytical marker for a product of (a) a process involving that compound as a reagent or (b) a process involving as reagents 1-(4-hydroxy-2-aminophenyl)-1-propanone and 4-piperidinopiperidinecarbamyl chloride under circumstances permitting these reagents to react to form 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate.
R1 in a compound of formula (VI) of the present invention is hydrogen, an alkyl, aralkyl, hydroxymethyl, carboxymethyl, acyloxymethyl or trialkylsilyl, e.g., trimethylsilyl, group, or a group xe2x80x94CH2NR3R4 where N is a linking nitrogen atom and where (a) R3 and R4 are independently selected from hydrogen and alkyl alkenyl, hydroxyalkyl and alkoxyalkyl groups; (b) R3 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group, and R4 is xe2x80x94COR5 where R5 is hydrogen or an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group; or (c) R3 and R4 taken together with the linking nitrogen atom form a saturated 3- to 7-member heterocyclic group. Also provided are salts of the compounds of formula (VI) with pharmaceutically acceptable anions.
Alkyl, alkenyl, aralkyl, acyl and alkoxy groups herein, unless otherwise defined, have 1-30, preferably 1-18, more preferably 1-6, carbon atoms. In particularly preferred compounds of formula (VI), R1 is a C1-4 alkyl, most preferably an ethyl, group.
Compounds of formula (VI) above exist in free base form and in various pharmaceutically acceptable salt forms, which are embodiments of the present invention.
Pharmaceutically acceptable salts of compounds of formula (VI) include without restriction salts of the following acids: hydrochloric, hydrobromic, sulfuric, methanesulfonic, phosphoric, nitric, benzoic, citric, tartaric, fumaric and maleic acids, and mono- and dicarboxylic acids of formula CH3xe2x80x94(CH2)nxe2x80x94COOH and HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0 to 4, for example malonic acid. The hydrochloride salt is particularly preferred.
In another embodiment of the invention a process is provided comprising a step of reacting 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate (the compound of formula (VI) where R1 is ethyl) or a salt thereof with 14CPT ((4S)-4-ethyl-7,8-dihydro-4-hydroxy-(1H)-pyrano[3,4-f]indolizine-3,6,10(4H)-trione), the compound of formula (I) above, to form irinotecan or the corresponding salt thereof.
This reaction can illustratively be carried out by beating 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate and 14CPT together in a suitable solvent, for example acetic acid. The product of the reaction can then be purified by a suitable chromatographic method and isolated, for example by crystallization from a suitable solvent medium. An illustrative example of a process of this embodiment of the invention is provided below in @Example 2.
Accordingly, the novel compound 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate or a salt thereof is a useful intermediate in a manufacturing process for irinotecan or a salt thereof.
Optionally, irinotecan or a salt thereof prepared by a process of the invention can be further processed to yield other camptothecin derivatives by methods known in the art. For example, irinotecan prepared as described herein can be subjected to hydrolysis in an acid medium, for example in presence of hydrochloric acid, to yield 7-ethyl-10-hydroxycamptothecin.
In yet another embodiment of the invention a process for preparing 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate is provided, comprising a step of reacting 1-(4-hydroxy-2-aminophenyl)-1-propanone (II) with 4-piperidinopiperidinecarbamyl chloride (IV).
This reaction can illustratively be carried out by mixing known compounds (II) and (IV) together in a suitable solvent, for example pyridine. Alternatively, a solvent system comprising methylene chloride, tetrahydrofuran, acetonitrile or the like together with a suitable base such as triethylamine or diisopropylethylamine can be used as a medium for the reaction. The product of the reaction can then be subjected to isolation and purification steps, illustratively those described in Example 1 below, to yield 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate.
In yet another embodiment of the invention, a pharmaceutical composition or drug substance is provided comprising (a) irinotecan and/or one or more pharmaceutically acceptable salts thereof in a therapeutically effective total amount, and (b) 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate and/or one or more salts thereof in at least a detectable amount. By a xe2x80x9ctherapeutically effectivexe2x80x9d amount of irinotecan or salt thereof is meant an amount useful as at least a single dosage amount for treatment of cancer. By a xe2x80x9cdetectablexe2x80x9d amount of 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate is meant a sufficient amount to give positive identification but not necessarily quantitation of the compound by any suitable analytical technique, for example HPLC.
Preferably according to this embodiment, the drug substance comprises not more than about 5%, more preferably not more than about 2.5% and most preferably not more than about 1% by weight of 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate. The presence of 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylatein a drug substance of this embodiment is useful as an analytical marker, providing evidence, for example, that the irinotecan with which it occurs has been prepared by (a) a process involving 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate as a reagent (e.g., the process described above and illustrated in Example 2 below) or (b) a process involving as reagents compounds (II) and (IV) under circumstances permitting these compounds to react to form 4-amino-3-propionylphenyl-1,4xe2x80x2-bipiperidine-1xe2x80x2-carboxylate.